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Combinatorial Aid for Underprivileged Scaffolds: Solution and Solid-phase Strategies for a Rapid and Efficient Access To Novel Aza-diketopiperazines (Aza-DKP)

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journal contribution
posted on 14.05.2012, 00:00 authored by Dominique Bonnet, Jean-François Margathe, Sally Radford, Elsa Pflimlin, Stéphanie Riché, Pete Doman, Marcel Hibert, A. Ganesan
An efficient solution-phase synthesis of aza-diketopiperazines (aza-DKP, triazinediones) is reported. A structurally diverse collection of c-[aza-alkylGly-Pro] derivatives and yet unreported 2,4,5-trisubstituted-1,2,4-triazine-3,6-diones has been synthesized starting from Fmoc-l-Pro-OH and various Fmoc-l-amino acids. To extend the practical value of this class of dipeptidomimetics, a general solid-phase synthesis approach amenable to library production was developed on both Wang-PS and HMBA-PS resins. The final acidic treatment of the resins in TFA/water mixture at room temperature enabled the rapid and quantitative cyclization/release highly pure triazinediones. The conformational preferences and the spatial organization of the three substituents of a representative 2,4,5-trisubstituted-1,2,4-triazine-3,6-dione were investigated by X-ray diffraction and 1H NMR spectroscopy.